Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

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React. Chem. Eng., 2016, Advance Article
DOI: 10.1039/C6RE00059B, Paper

Open Access

  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Nicholas Holmes, Geoffrey R. Akien, A. John Blacker, Robert L. Woodward, Rebecca E. Meadows, Richard A. Bourne
Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions.

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions. This technique has been applied to the final bond-forming step in the synthesis of AZD9291, an irreversible epidermal growth factor receptor kinase inhibitor developed by AstraZeneca. A four parameter optimisation of a telescoped amide coupling followed by an elimination reaction was achieved using at-line high performance liquid chromatography. Optimisations were initially carried out on a model compound (2,4-dimethoxyaniline) and the data used to track the formation of various impurities and ultimately propose a mechanism for their formation. Our protocol could then be applied to the optimisation of the 2-step telescoped reaction to synthesise AZD9291 in 89% yield.

http://pubs.rsc.org/en/Content/ArticleLanding/2016/RE/C6RE00059B#!divAbstract

///////Self-optimisation, synthesis, EGFR kinase inhibitor, AZD9291,  automated flow reactor

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